Biodefense Implications of New-World Hantaviruses

Abstract

Hantaviruses, part of the Bunyaviridae family, are a genus of negative-sense, single-stranded RNA viruses that cause two major diseases: New-World Hantavirus Cardiopulmonary Syndrome and Old-World Hemorrhagic Fever with Renal Syndrome. Hantaviruses generally are found worldwide with each disease corresponding to their respective hemispheres. New-World Hantaviruses spread by specific rodent-host reservoirs and are categorized as emerging viruses that pose a threat to global health and security due to their high mortality rate and ease of transmission. Incidentally, reports of Hantavirus categorization as a bioweapon are often contradicted as both US National Institute of Allergy and Infectious Diseases and the Centers for Disease Control and Prevention refer to them as Category A and C bioagents respectively, each retaining qualitative levels of importance and severity. Concerns of Hantavirus being engineered into a novel bioagent has been thwarted by Hantaviruses being difficult to culture, isolate, and purify limiting its ability to be weaponized. However, the natural properties of Hantaviruses pose a threat that can be exploited by conventional and unconventional forces. This review seeks to clarify the categorization of Hantaviruses as a bioweapon, whilst defining the practicality of employing New-World Hantaviruses and their effect on armies, infrastructure, and civilian targets.

Keywords: Andes Virus; Sin Nombre Virus; biodefense; bioterrorism; hantavirus; hantavirus cardiopulmonary syndrome; transmission; viral pandemic.

FIGURE 1

Annual average cases of new-world hantaviruses in the western hemisphere. North America (A) although Mexico has reported there being no HCPS cases, seroprevalence of hantaviruses exists in 10.15% of rodents, much of which occurs in Mexican states that border the United States where 299 cases of HCPS were reported between 1993 and 2017. Seropositive humans were identified, and the lack of reporting is attributed to the febrile disease being misconstrued with other illnesses (Vigueras-Galvan et al., 2019). This is very similar to other Central Latin American nations which have very limited reporting or insufficient data but show seroprevalence of hantavirus in rodents, up to 20.8% in Honduras as an example (Knust and Rollin, 2013; Rovida et al., 2013; Montoya-Ruiz et al., 2014; Drebot et al., 2015). Gray locations indicate countries with no reporting of hantavirus. South America (B) most cases occurred in rural or forested environments with farming being a major concern. Reporting is an issue as the actual annual cases for Brazil, Columbia, and Venezuela are considered to be significantly higher (Figueiredo et al., 2014; Montoya-Ruiz et al., 2014; Goeijenbier et al., 2015; Riquelme et al., 2015; Jiang et al., 2017; Matheus et al., 2017; Fonseca et al., 2018; Alonso et al., 2019; Escalera-Antezana et al., 2020). Averages of HCPS-causing hantavirus cases taken from studies carried out between 2000 and 2019.

FIGURE 2

Hantavirus structure. Hantaviruses are enveloped with a lipid bilayer containing Glycoprotein spikes assemblies comprised of Gn and Gc Glycoproteins. Contained within the envelope are the equimolar amounts of N Protein packaged S (small), M (medium), and L (large) segments vRNA, which are associated with an RdRp (Hussein et al., 2011; Hepojoki et al., 2012). SNV structure is generally spherical with a dense envelope (Goldsmith et al., 1995). N Protein forms trimers that selectively encapsidates the negative-sense vRNA into RNPs and assists in its panhandle formation for packaging (Mir and Panganiban, 2004).

FIGURE 3

HCPS-causing hantavirus life cycle. Pathogenic HCPS-causing hantaviruses such as SNV or ANDV will first bind to β₃-Integrin receptors on endothelial cells which will mediate endocytosis. The formation of an early endosome helps traffic the virion to the Golgi Complex. Following a pH-mediated membrane fusion, the now late endosome disassembles and releases the ribonucleoproteins (RNPs) near the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC). The RNPs disassemble and the RdRp carries out transcription and replication in the cytoplasm, cleaving cellular mRNA to form capped primers to initiate viral mRNA transcription. Transcribed S, M, and L Segment mRNA is translated into N Protein, GPC (and then into co-translated Gn and Gc Glycoproteins), and RdRp respectively. Negative-sense vRNA serves as the template for the transcription of mRNA. RdRp undergoes a transition from transcription to the replication of negative-sense vRNA which is considered to be mediated by the increase in free N Protein concentration (Jonsson and Schmaljohn, 2001). New-World Hantaviruses will be assembled at the plasma membrane compared to Old-World Hantaviruses that are assembled at the Golgi complex (Muyangwa et al., 2015). Nascent virions bud from the plasma membrane.